The present invention relates to a novel method for producing an intermediate of biotin and a novel method for producing biotin in which the intermediate obtained by the method for producing an intermediate is used.
Biotin is a water-soluble vitamin used in medicines from which diabetes-preventing effect or the like is expected, and in feed additives or the like.
The biotin has a very long production process. Therefore, even the intermediate is produced through many processes. For example, even a thiolactone compound represented by the following formula (5)

(wherein, R1 and R2 may be the same or different and each represents a hydrogen atom or a protecting group of an ureylene group), which is a representative intermediate of the biotin, is produced through very long processes as described below (see Patent Document 1). In the following processes, an example of an occasion when R1 and R2 are benzyl groups (Bn groups) (examples 1 and 3 of Patent Document 1) is shown.

In the examples of Patent Document 1, a method is shown in which at first, an optically active amine such as α-phenethylamine ((R)-(+)-1-methylbenzylamine) is reacted with 1,3-dibenzyl-2-imidazolidone-cis-4,5-dicarboxylic acid to produce 1,3-dibenzyl-5-(α-phenethyl)-hexahydropyrrolo [3,4-a] imidazole-2,4,6-trione (step 1). Then, reduction (step 2), cyclization (step 3), and a thiation reaction (step 4) of 1,3-dibenzyl-5-(α-phenethyl)-hexahydropyrrolo [3,4-a] imidazole-2,4,6-trione are carried out to produce the thiolactone compound comprising a benzyl group. Besides, in Patent Document 1, it is shown that reactions of 7 processes are further carried out for the thiolactone compound, and the biotin which is a final product is obtained.
As described above, biotin is produced through a great many processes. Therefore, in order to lower the production cost of biotin, improvement of the production cost of the intermediate in each process, that is, improvement of the yield of each intermediate is also important.
However, it is known that, even in the processes above, in the reduction reaction (step 2), in addition to the amide alcohol compound which can eventually become biotin, an optical isomer of the amide alcohol compound is generated as an impurity, and the yield of the amide alcohol compound is decreased. The optical isomer impurity cannot become biotin, so that the yield decrease of the amide alcohol compound becomes a problem. As shown in example 3 of Patent Document 1, the amide alcohol compound, which is obtained by recrystallizing the product that is obtained in step 2 and comprises the impurity by a mixed solvent of water and isopropanol, is eventually obtained with a yield of about 50% only.
Patent Document 1: U.S. Pat. No. 3,876,656